Transfer Learning Reveals Cancer-Associated Fibroblasts Are Associated with Epithelial-Mesenchymal Transition and Inflammation in Cancer Cells in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by an immunosuppressive tumor microenvironment enriched with cancer-associated fibroblasts (CAF). This study used a convergence approach to identify tumor cell and CAF interactions through the integration of single-cell data from human tumors with human organoid coculture experiments. Analysis of a comprehensive atlas of PDAC single-cell RNA sequencing data indicated that CAF density is associated with increased inflammation and epithelial-mesenchymal transition (EMT) in epithelial cells. Transfer learning using transcriptional data from patient-derived organoid and CAF cocultures provided in silico validation of CAF induction of inflammatory and EMT epithelial cell states. Further experimental validation in cocultures demonstrated integrin beta 1 (ITGB1) and vascular endothelial factor A (VEGFA) interactions with neuropilin-1 mediating CAF-epithelial cell cross-talk. Together, this study introduces transfer learning from human single-cell data to organoid coculture analyses for experimental validation of discoveries of cell-cell cross-talk and identifies fibroblast-mediated regulation of EMT and inflammation. SIGNIFICANCE: Adaptation of transfer learning to relate human single-cell RNA sequencing data to organoid-CAF cocultures facilitates discovery of human pancreatic cancer intercellular interactions and uncovers cross-talk between CAFs and tumor cells through VEGFA and ITGB1.

Accurate non-invasive grading of nonfunctional pancreatic neuroendocrine tumors with a CT derived radiomics signature.

PURPOSE: The purpose of this study was to develop a radiomics-signature using computed tomography (CT) data for the preoperative prediction of grade of nonfunctional pancreatic neuroendocrine tumors (NF-PNETs). MATERIALS AND METHODS: A retrospective study was performed on patients undergoing resection for NF-PNETs between 2010 and 2019. A total of 2436 radiomic features were extracted from arterial and venous phases of pancreas-protocol CT examinations. Radiomic features that were associated with final pathologic grade observed in the surgical specimens were subjected to joint mutual information maximization for hierarchical feature selection and the development of the radiomic-signature. Youden-index was used to identify optimal cutoff for determining tumor grade. A random forest prediction model was trained and validated internally. The performance of this tool in predicting tumor grade was compared to that of EUS-FNA sampling that was used as the standard of reference. RESULTS: A total of 270 patients were included and a fusion radiomic-signature based on 10 selected features was developed using the development cohort (n = 201). There were 149 men and 121 women with a mean age of 59.4 ± 12.3 (standard deviation) years (range: 23.3-85.0 years). Upon internal validation in a new set of 69 patients, a strong discrimination was observed with an area under the curve (AUC) of 0.80 (95% confidence interval [CI]: 0.71-0.90) with corresponding sensitivity and specificity of 87.5% (95% CI: 79.7-95.3) and 73.3% (95% CI: 62.9-83.8) respectively. Of the study population, 143 patients (52.9%) underwent EUS-FNA. Biopsies were non-diagnostic in 26 patients (18.2%) and could not be graded due to insufficient sample in 42 patients (29.4%). In the cohort of 75 patients (52.4%) in whom biopsies were graded the radiomic-signature demonstrated not different AUC as compared to EUS-FNA (AUC: 0.69 vs. 0.67; P = 0.723), however greater sensitivity (i.e., ability to accurately identify G2/3 lesion was observed (80.8% vs. 42.3%; P < 0.001). CONCLUSION: Non-invasive assessment of tumor grade in patients with PNETs using the proposed radiomic-signature demonstrated high accuracy. Prospective validation and optimization could overcome the commonly experienced diagnostic uncertainty in the assessment of tumor grade in patients with PNETs and could facilitate clinical decision-making.

Deep neural network-based segmentation of normal and abnormal pancreas on abdominal CT: evaluation of global and local accuracies.

PURPOSE: Delay in diagnosis can contribute to poor outcomes in pancreatic ductal adenocarcinoma (PDAC), and new tools for early detection are required. Recent application of artificial intelligence to cancer imaging has demonstrated great potential in detecting subtle early lesions. The aim of the study was to evaluate global and local accuracies of deep neural network (DNN) segmentation of normal and abnormal pancreas with pancreatic mass. METHODS: Our previously developed and reported residual deep supervision network for segmentation of PDAC was applied to segment pancreas using CT images of potential renal donors (normal pancreas) and patients with suspected PDAC (abnormal pancreas). Accuracy of DNN pancreas segmentation was assessed using DICE simulation coefficient (DSC), average symmetric surface distance (ASSD), and Hausdorff distance 95% percentile (HD95) as compared to manual segmentation. Furthermore, two radiologists semi-quantitatively assessed local accuracies and estimated volume of correctly segmented pancreas. RESULTS: Forty-two normal and 49 abnormal CTs were assessed. Average DSC was 87.4 ± 3.1% and 85.5 ± 3.2%, ASSD 0.97 ± 0.30 and 1.34 ± 0.65, HD95 4.28 ± 2.36 and 6.31 ± 6.31 for normal and abnormal pancreas, respectively. Semi-quantitatively, ≥95% of pancreas volume was correctly segmented in 95.2% and 53.1% of normal and abnormal pancreas by both radiologists, and 97.6% and 75.5% by at least one radiologist. Most common segmentation errors were made on pancreatic and duodenal borders in both groups, and related to pancreatic tumor including duct dilatation, atrophy, tumor infiltration and collateral vessels. CONCLUSION: Pancreas DNN segmentation is accurate in a majority of cases, however, minor manual editing may be necessary; particularly in abnormal pancreas.

Concepts and techniques for revascularization of replaced hepatic arteries in pancreatic head resections.

BACKGROUND: The relationship of pancreatic ductal adenocarcinoma (PDAC) to important peripancreatic vasculature dictates resectability. As per the current guidelines, tumors with extensive, unreconstructible venous or arterial involvement are staged as unresectable locally advanced pancreatic cancer (LAPC). The introduction of effective multiagent chemotherapy and development of surgical techniques, have renewed interest in local control of PDAC. High-volume centers have demonstrated safe resection of short-segment encasement of the common hepatic artery. Knowledge of the unique anatomy of the patient's vasculature is important in surgical planning of these complex resections. Hepatic artery anomalies are common and insufficient knowledge can result in iatrogenic vascular injury during surgery. METHODS AND RESULTS: Here, we discuss different strategies to resect and reconstruct replaced hepatic arteries during pancreatectomy for PDAC to ensure restoration of adequate blood flow to the liver. Strategies include various arterial transpositions, in-situ interposition grafts and the use of extra-anatomic jump grafts. CONCLUSION: These surgical techniques allow more patients to undergo the only available curative treatment currently available for PDAC. Moreover, these improvements in surgical techniques highlight the shortcoming of current resectability criteria, which rely mainly on local tumor involvement and technical resectability, and disregards tumor biology.

Predicting post-recurrence survival for patients with pancreatic cancer recurrence after primary resection: A Bi-institutional validated risk classification.

BACKGROUND: Over 80% of patients will develop disease recurrence after radical resection of pancreatic ductal adenocarcinoma (PDAC). This study aims to develop and validate a clinical risk score predicting post-recurrence survival (PRS) at time of recurrence. METHODS: All patients who had recurrence after undergoing pancreatectomy for PDAC at the Johns Hopkins Hospital or at the Regional Academic Cancer Center Utrecht during the study period were included. Cox proportional hazard model was used to develop the risk model. Performance of the final model was assessed in a test set after internal validation. RESULTS: Of 718 resected PDAC patients, 72% had recurrence after a median follow-up of 32 months. The median overall survival was 21 months and the median PRS was 9 months. Prognostic factors associated with shorter PRS were age (hazard ratio [HR] 1.02; 95% confidence interval [95%CI] 1.00-1.04), multiple-site recurrence (HR 1.57; 95%CI 1.08-2.28), and symptoms at time of recurrence (HR 2.33; 95%CI 1.59-3.41). Recurrence-free survival longer than 12 months (HR 0.55; 95%CI 0.36-0.83), FOLFIRINOX and gemcitabine-based adjuvant chemotherapy (HR 0.45; 95%CI 0.25-0.81; HR 0.58; 95%CI 0.26-0.93, respectively) were associated with a longer PRS. The resulting risk score had a good predictive accuracy (C-index: 0.73). CONCLUSION: This study developed a clinical risk score based on an international cohort that predicts PRS in patients who underwent surgical resection for PDAC. This risk score will become available on www.evidencio.com and can help clinicians with patient counseling on prognosis.

Morphology-guided transcriptomic analysis of human pancreatic cancer organoids reveals microenvironmental signals that enhance invasion.

Pancreatic ductal adenocarcinoma (PDAC) frequently presents with metastasis, but the molecular programs in human PDAC cells that drive invasion are not well understood. Using an experimental pipeline enabling PDAC organoid isolation and collection based on invasive phenotype, we assessed the transcriptomic programs associated with invasion in our organoid model. We identified differentially expressed genes in invasive organoids compared with matched noninvasive organoids from the same patients, and we confirmed that the encoded proteins were enhanced in organoid invasive protrusions. We identified 3 distinct transcriptomic groups in invasive organoids, 2 of which correlated directly with the morphological invasion patterns and were characterized by distinct upregulated pathways. Leveraging publicly available single-cell RNA-sequencing data, we mapped our transcriptomic groups onto human PDAC tissue samples, highlighting differences in the tumor microenvironment between transcriptomic groups and suggesting that non-neoplastic cells in the tumor microenvironment can modulate tumor cell invasion. To further address this possibility, we performed computational ligand-receptor analysis and validated the impact of multiple ligands (TGF-ß1, IL-6, CXCL12, MMP9) on invasion and gene expression in an independent cohort of fresh human PDAC organoids. Our results identify molecular programs driving morphologically defined invasion patterns and highlight the tumor microenvironment as a potential modulator of these programs.

Distal Pancreatectomy With En Bloc Celiac Axis Resection (DP-CAR) for Locally Advanced Pancreatic Cancer: A Safe and Effective Procedure.

OBJECTIVE: To determine perioperative and oncologic outcomes after distal pancreatectomy with en bloc resection of the celiac axis (DP-CAR). BACKGROUND: DP-CAR can be used in a selective group of patients to resect locally advanced pancreatic cancer involving the celiac axis or common hepatic artery without arterial reconstruction by preserving retrograde blood flow via the gastroduodenal artery to the liver and stomach. METHODS: We analyzed all consecutive patients who had undergone DP-CAR between May 2003 and April 2022 at a tertiary hospital specialized in pancreatic surgery and present one of the largest single-center studies. RESULTS: A total of 71 patients underwent DP-CAR. Additional venous resection (VR) of the mesenterico-portal axis was performed in 31 patients (44%) and multivisceral resection (MVR) in 42 patients (59%). Margin-free (R0) resection was achieved in 40 patients (56%). The overall 90-day mortality rate was 8.4% for the entire patient cohort. After a cumulated experience of 16 cases, the 90-day mortality dropped to 3.6% in the following 55 patients. Extended procedures with (+) additional MVR with or without (+/-) VR resulted in higher major morbidity (Clavien-Dindo ≥IIIB; standard DP-CAR: 19%; DP-CAR + MVR +/- VR: 36%) and higher 90-day mortality (standard DP-CAR: 0%; DP-CAR + MVR +/- VR: 11%). Median overall survival after DP-CAR was 28 months. CONCLUSIONS: DP-CAR is a safe and effective procedure but requires experience. Frequently, surgical resection has to be extended with MVR and VR to accomplish tumor resection, which results in promising oncologic outcomes. However, extended resections were associated with increased morbidity and mortality.

Cancer-cell-derived sialylated IgG as a novel biomarker for predicting poor pathological response to neoadjuvant therapy and prognosis in pancreatic cancer.

BACKGROUND: Neoadjuvant therapy (NAT) is increasingly applied in pancreatic ductal adenocarcinoma (PDAC); however, accurate prediction of therapeutic response to NAT remains a pressing clinical challenge. Cancer-cell-derived sialylated immunoglobulin G (SIA-IgG) was previously identified as a prognostic biomarker in PDAC. This study aims to explore whether SIA-IgG expression in treatment-naïve fine needle aspirate (FNA) biopsy specimens could predict the pathological response (PR) to NAT for PDAC. METHODS: Endoscopic ultrasonography-guided FNA biopsy specimens prior to NAT were prospectively obtained from 72 patients with PDAC at the Johns Hopkins Hospital. SIA-IgG expression of PDAC specimens was assessed by immunohistochemistry. Associations between SIA-IgG expression and PR, as well as patient prognosis, were analyzed. A second cohort enrolling surgically resected primary tumor specimens from 79 patients with PDAC was used to validate the prognostic value of SIA-IgG expression. RESULTS: SIA-IgG was expressed in 58.3% of treatment-naïve FNA biopsies. Positive SIA-IgG expression at diagnosis was associated with unfavorable PR and can serve as an independent predictor of PR. The sensitivity and specificity of SIA-IgG expression in FNA specimens in predicting an unfavorable PR were 63.9% and 80.6%, respectively. Both positive SIA-IgG expression in treatment-naïve FNA specimens and high SIA-IgG expression in surgically resected primary tumor specimens were significantly associated with shorter survival. CONCLUSIONS: Assessment of SIA-IgG on FNA specimens prior to NAT may help predict PR for PDAC. Additionally, SIA-IgG expression in treatment-naïve FNA specimens and surgically resected primary tumor specimens were predictive of the prognosis for PDAC.

Resected Early-Onset Pancreatic Cancer: Practices and Outcomes in an International Dual-Center Study.

BACKGROUND: Early-onset pancreatic cancer (EOPC), defined as age ≤ 45 years at diagnosis, accounts for 3% of all pancreatic cancer cases. Although differences in tumor biology have been suggested, available data are sparse and specific treatment recommendations are lacking. This study explores the clinicopathological features and oncologic outcomes of resected EOPC. PATIENTS AND METHODS: Patients with EOPC undergoing resection between 2002 and 2018 were identified from the Heidelberg University Hospital and Johns Hopkins University registries. Median overall survival (OS) and recurrence-free survival (RFS) were analyzed, and prognostic factors were identified. RESULTS: The final cohort included 164 patients, most of whom had pancreatic ductal adenocarcinoma (PDAC, n = 136; 82.9%) or IPMN-associated pancreatic cancer (n = 17; 10.4%). Twenty (12.1%) patients presented with stage 1 disease, 42 (25.6%) with stage 2, 75 (45.7%) with stage 3, and 22 (13.4%) with oligometastatic stage 4 disease. Most patients underwent upfront resection (n = 113, 68.9%), whereas 51 (31.1%) individuals received preoperative treatment. Median OS and RFS were 26.0 and 12.4 months, respectively. Stage-specific median survival was 70.6, 41.8, 23.8, and 16.9 months for stage 1, 2, 3, and 4 tumors, respectively. Factors independently associated with shorter OS and RFS were R1 resections and AJCC stages 3 and 4. Notably, AJCC 3-N2 and AJCC 3-T4 tumors had a median OS of 20 months versus 29.5 months, respectively. CONCLUSION: Despite frequently presenting with advanced disease, oncologic outcomes in EOPC patients are satisfactory even in locally advanced cancers, justifying aggressive surgical approaches. Further research is needed to tailor current guidelines to this rare population.

Conduits in Vascular Pancreatic Surgery: Analysis of Clinical Outcomes, Operative Techniques, and Graft Performance.

OBJECTIVES: We analyze successes and failures of pushing the boundaries in vascular pancreatic surgery to establish safety of conduit reconstructions. BACKGROUND: Improved systemic control from chemotherapy in pancreatic cancer is increasing the demand for surgical solutions of extensive local vessel involvement, but conduit-specific data are scarce. METHODS: We identified 63 implanted conduits (41% autologous vessels, 37% allografts, 18% PTFE) in 56 pancreatic resections of highly selected cancer patients between October 2013 and July 2020 from our prospectively maintained database. Assessed parameters were survival, perioperative complications, operative techniques (anatomic and extra-anatomic routes), and conduit patency. RESULTS: For vascular reconstruction, 25 arterial and 38 venous conduits were utilized during 39 pancreatoduodenectomies, 14 distal pancreatectomies, and 3 total pancreatectomies. The median postoperative survival was 2 years. A Clavien-Dindo grade ≥IIIa complication was apparent in 50% of the patients with a median Comprehensive Complication Index of 29.6. The 90-day mortality in this highly selected cohort was 9%. Causes of mortality were conduit related in 3 patients, late postpancreatectomy hemorrhage in 1 patient, and early liver metastasis in 1 patient. Image-based patency rates of conduits were 66% and 45% at postoperative days 30 and 90, respectively. CONCLUSIONS: Our perioperative mortality of vascular pancreatic surgery with conduits in the arterial or venous system is 9%. Reconstructions are technically feasible with different anatomic and extra-anatomic strategies, while identifying predictors of early conduit occlusion remains challenging. Optimizing reconstructed arterial and venous hemodynamics in the context of pancreatic malignancy will enable long-term survival in more patients responsive to chemotherapies.

Surgical Decision-Making in Pancreatic Ductal Adenocarcinoma: Modeling Prognosis Following Pancreatectomy in the Era of Induction and Neoadjuvant Chemotherapy.

OBJECTIVE: To develop a predictive model of oncologic outcomes for patients with pancreatic ductal adenocarcinoma (PDAC) undergoing resection after neoadjuvant or induction chemotherapy use. BACKGROUND: Early recurrence following surgical resection for PDAC is common. The use of neoadjuvant chemotherapy prior to resection may increase the likelihood of long-term systemic disease control. Accurately characterizing an individual's likely oncologic outcome in the perioperative setting remains challenging. METHODS: Data from patients with PDAC who received chemotherapy prior to pancreatectomy at a single high-volume institution between 2007 and 2018 were captured in a prospectively collected database. Core clinicopathologic data were reviewed for accuracy and survival data were abstracted from the electronic medical record and national databases. Cox-proportional regressions were used to model outcomes and develop an interactive prognostic tool for clinical decision-making. RESULTS: A total of 581 patients were included with a median overall survival (OS) and recurrence-free survival (RFS) of 29.5 (26.5-32.5) and 16.6 (15.8-17.5) months, respectively. Multivariable analysis demonstrates OS and RFS were associated with type of chemotherapeutic used andthe number of chemotherapy cycles received preoperatively. Additional factors contributing to survival models included: tumor grade, histopathologic response to therapy, nodal status, and administration of adjuvant chemotherapy. The models were validated using an iterative bootstrap method and with randomized cohort splitting. The models were well calibrated with concordance indices of 0.68 and 0.65 for the final OS and RFS models, respectively. CONCLUSION: We developed an intuitive and dynamic decision-making tool that can be useful in estimating OS, RFS, and location-specific disease recurrence rates. This prognostic tool may add value to patient care in discussing the benefits associated with surgical resection for PDAC.

A Delay in Adjuvant Therapy Is Associated With Worse Prognosis Only in Patients With Transitional Circulating Tumor Cells After Resection of Pancreatic Ductal Adenocarcinoma.

OBJECTIVES: The aim of the study was to assess the association of circulating tumor cells (CTCs) with survival as a biomarker in pancreatic ductal adenocarcinoma (PDAC) within the context of a delay in the initiation of adjuvant therapy. BACKGROUND: Outcomes in patients with PDAC remain poor and are driven by aggressive systemic disease. Although systemic therapies improve survival in resected patients, factors such as a delay in the initiation of adjuvant therapy are associated with worse outcomes. CTCs have previously been shown to be predictive of survival. METHODS: A retrospective study was performed on PDAC patients enrolled in the prospective CircuLating tUmor cellS in pancreaTic cancER trial (NCT02974764) on CTC-dynamics at the Johns Hopkins Hospital. CTCs were isolated based on size (isolation by size of epithelial tumor cells; Rarecells) and counted and characterized by subtype using immunofluorescence. The preoperative and postoperative blood samples were used to identify 2 CTC types: epithelial CTCs (eCTCs), expressing pancytokeratin, and transitional CTCs (trCTCs), expressing both pancytokeratin and vimentin. Patients who received adjuvant therapy were compared with those who did not. A delay in the receipt of adjuvant therapy was defined as the initiation of therapy ≥8 weeks after surgical resection. Clinicopathologic features, CTCs characteristics, and outcomes were analyzed. RESULTS: Of 101 patients included in the study, 43 (42.5%) experienced a delay in initiation and 20 (19.8%) did not receive adjuvant therapy. On multivariable analysis, the presence of trCTCs ( P =0.002) and the absence of adjuvant therapy ( P =0.032) were associated with worse recurrence-free survival (RFS). Postoperative trCTC were associated with poorer RFS, both in patients with a delay in initiation (12.4 vs 17.9 mo, P =0.004) or no administration of adjuvant chemotherapy (3.4 vs NR, P =0.016). However, it was not associated with RFS in patients with timely initiation of adjuvant chemotherapy ( P =0.293). CONCLUSIONS: Postoperative trCTCs positivity is associated with poorer RFS only in patients who either experience a delay in initiation or no receipt of adjuvant therapy. This study suggests that a delay in the initiation of adjuvant therapy could potentially provide residual systemic disease (trCTCs) a window of opportunity to recover from the surgical insult. Future studies are required to validate these findings and explore the underlying mechanisms involved.

Pancreatic Surgery in Children: Complex, Safe and Effective.

OBJECTIVE: The aim of this study is to assess indications for and report outcomes of pancreatic surgery in pediatric patients. BACKGROUND: Indications for pancreatic surgery in children are rare and data on surgical outcomes after pediatric pancreatic surgery are scarce. METHODS: All children who underwent pancreatic surgery at a tertiary hospital specializing in pancreatic surgery between 2003 and 2022 were identified from a prospectively maintained database. Indications, surgical procedures, and perioperative as well as long-term outcomes were analyzed. RESULTS: In total, 73 children with a mean age of 12.8 years (range: 4 months-18 years) underwent pancreatic surgery during the observation period. Indications included chronic pancreatitis (n=35), pancreatic tumors (n=27), and pancreatic trauma (n=11). Distal pancreatectomy was the most frequently performed procedure (n=23), followed by pancreatoduodenectomy (n=19), duodenum-preserving pancreatic head resection (n=10), segmental pancreatic resection (n=7), total pancreatectomy (n=3), and others (n=11). Postoperative morbidity occurred in 25 patients (34.2%), including 7 cases (9.6%) with major complications (Clavien-Dindo≥III). There was no postoperative (90-day) mortality. The 5-year overall survival was 90.5%. The 5-year event-free survival of patients with chronic pancreatitis was 85.7%, and 69.0% for patients with pancreatic tumors. CONCLUSION: This is the largest single-center study on pediatric pancreatic surgery in a Western population. Pediatric pancreatic surgery can be performed safely. Centralization in pancreatic centers with high expertise in surgery of adult and pediatric patients is important as it both affords the benefits of pancreatic surgery experience and ensures that surgical management is adapted to the specific needs of children.

Multi-omic analyses of changes in the tumor microenvironment of pancreatic adenocarcinoma following neoadjuvant treatment with anti-PD-1 therapy.

Successful pancreatic ductal adenocarcinoma (PDAC) immunotherapy necessitates optimization and maintenance of activated effector T cells (Teff). We prospectively collected and applied multi-omic analyses to paired pre- and post-treatment PDAC specimens collected in a platform neoadjuvant study of granulocyte-macrophage colony-stimulating factor-secreting allogeneic PDAC vaccine (GVAX) vaccine ± nivolumab (anti-programmed cell death protein 1 [PD-1]) to uncover sensitivity and resistance mechanisms. We show that GVAX-induced tertiary lymphoid aggregates become immune-regulatory sites in response to GVAX + nivolumab. Higher densities of tumor-associated neutrophils (TANs) following GVAX + nivolumab portend poorer overall survival (OS). Increased T cells expressing CD137 associated with cytotoxic Teff signatures and correlated with increased OS. Bulk and single-cell RNA sequencing found that nivolumab alters CD4+ T cell chemotaxis signaling in association with CD11b+ neutrophil degranulation, and CD8+ T cell expression of CD137 was required for optimal T cell activation. These findings provide insights into PD-1-regulated immune pathways in PDAC that should inform more effective therapeutic combinations that include TAN regulators and T cell activators.

Predictors, Patterns, and Timing of Recurrence Provide Insight into the Disease Biology of Invasive Carcinomas Arising in Association with Intraductal Papillary Mucinous Neoplasms.

OBJECTIVES: To identify predictors, patterns, and timing of recurrence after resection of invasive carcinomas arising in association with an IPMN. BACKGROUND: Postoperative management of an invasive carcinoma arising in association with an intraductal papillary mucinous neoplasm (IPMN), a biologically distinct entity from PanIN-derived pancreatic ductal adenocarcinoma (PDAC), remains largely based on guidelines for PanIN-derived PDAC. To minimize treatment failure and inform disease-specific management, cancer recurrence must be better characterized. METHODS: Patients were identified from a prospectively maintained registry between 1996 and 2018. Predictors of recurrence were evaluated by employing Cox regression models to determine risk-adjusted hazard ratios (HR) with 95% confidence intervals (95%CI). The patterns and timing of recurrence were recognized and compared utilizing a log-rank test, respectively. RESULTS: Of the 213 patients included, 92 (43.2%) recurred with a median RFS of 23.7 months (16.7-30.7). The predominant pattern of recurrence included any systemic (65.2%). The median time to local recurrence was longer than systemic (21.6 versus 11.4 months, p = 0.05). Poor differentiation [HR: 3.01, 95%CI (1.06-8.61)] and nodal disease [N1, HR: 2.23, 95%CI (1.12-4.60); and N2, HR: 5.67 95%CI (2.93-10.99)] emerged as independent predictors of systemic recurrence. For local-specific recurrences, poor differentiation [HR: 3.73, 95%CI (1.04-13.45)] and an R1 margin [high-grade dysplasia or invasive carcinoma; HR: 2.66, 95%CI (1.14-6.21)] emerged as independent predictors. CONCLUSIONS: The predominant pattern of recurrence after resection of invasive carcinomas arising in association with IPMNs is systemic, and occurs earlier than local recurrence. Poor differentiation and nodal disease are associated with systemic recurrence while poor differentiation and an R1 margin are associated with local recurrence. Future studies should investigate the role of systemic (chemotherapy) versus local (radiation) therapies and surveillance strategies in a personalized manner.

Postoperative Chemotherapy is Associated with Improved Survival in Patients with Node-Positive Pancreatic Ductal Adenocarcinoma After Neoadjuvant Therapy.

BACKGROUND: Postoperative chemotherapy following pancreatic cancer resection is the standard of care. The utility of postoperative chemotherapy for patients who receive neoadjuvant therapy (NAT) is unclear. METHODS: Patients who underwent pancreatectomy after NAT with FOLFIRINOX or gemcitabine-based chemotherapy for non-metastatic pancreatic adenocarcinoma (2015-2019) were identified. Patients who received less than 2 months of neoadjuvant chemotherapy or died within 90 days from surgery were excluded. RESULTS: A total of 427 patients (resectable, 22.2%; borderline resectable, 37.9%; locally advanced, 39.8%) were identified with the majority (69.3%) receiving neoadjuvant FOLFIRINOX. Median duration of NAT was 4.1 months. Following resection, postoperative chemotherapy was associated with an improved median overall survival (OS) (28.7 vs. 20.4 months, P = 0.006). Risk-adjusted multivariable modeling showed negative nodal status (N0), favorable pathologic response (College of American Pathologists score 0 & 1), and receipt of postoperative chemotherapy to be independent predictors of improved OS. Regimen, duration, and number of cycles of NAT were not significant predictors. Thirty-four percent (60/176) of node-positive and 50.1% (126/251) of node-negative patients did not receive postoperative chemotherapy due to poor functional status, postoperative complications, and patient preference. Among patients with node-positive disease, postoperative chemotherapy was associated with improved median OS (27.2 vs. 10.5 months, P < 0.001). Among node-negative patients, postoperative chemotherapy was not associated with a survival benefit (median OS, 30.9 vs. 36.9 months; P = 0.406). CONCLUSION: Although there is no standard NAT regimen for patients with pancreatic cancer, postoperative chemotherapy following NAT and resection appears to be associated with improved OS for patients with node-positive disease.

The Impact of the COVID-19 Pandemic on Multidisciplinary Clinics: A High-Volume Pancreatic Cancer Center Experience.

The unprecedented impact of the Sars-CoV-2 pandemic (COVID-19) has strained the healthcare system worldwide. The impact is even more profound on diseases requiring timely complex multidisciplinary care such as pancreatic cancer. Multidisciplinary care teams have been affected significantly in multiple ways as healthcare teams collectively acclimate to significant space limitations and shortages of personnel and supplies. As a result, many patients are now receiving suboptimal remote imaging for diagnosis, staging, and surgical planning for pancreatic cancer. In addition, the lack of face-to-face interactions between the physician and patient and between multidisciplinary teams has challenged patient safety, research investigations, and house staff education. In this study, we discuss how the COVID-19 pandemic has transformed our high-volume pancreatic multidisciplinary clinic, the unique challenges faced, as well as the potential benefits that have arisen out of this situation. We also reflect on its implications for the future during and beyond the pandemic as we anticipate a hybrid model that includes a component of virtual multidisciplinary clinics as a means to provide accessible world-class healthcare for patients who require complex oncologic management.